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Biperiden and mepazine effectively inhibit MALT1 activity and tumor growth in pancreatic cancer
Author(s) -
Konczalla Leonie,
Perez Daniel R.,
Wenzel Nadine,
WoltersEisfeld Gerrit,
Klemp Clarissa,
Lüddeke Johanna,
Wolski Annika,
Landschulze Dirk,
Meier Chris,
Buchholz Anika,
Yao Dichao,
Hofmann Bianca T.,
Graß Julia K.,
Spriestersbach Sarah L.,
Grupp Katharina,
Schumacher Udo,
Betzel Christian,
Kapis Svetlana,
Nuguid Theresa,
Steinberg Pablo,
Püschel Klaus,
Sauter Guido,
Bockhorn Maximillian,
Uzunoglu Faik G.,
Izbicki Jakob R.,
Güngör Cenap,
El Gammal Alexander T.
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32567
Subject(s) - pancreatic cancer , cancer research , apoptosis , in vivo , mediator , cancer , cell growth , medicine , pharmacology , biology , biochemistry , microbiology and biotechnology
MALT1 is a key mediator of NF‐κB signaling and a main driver of B‐cell lymphomas. Remarkably, MALT1 is expressed in the majority of pancreatic ductal adenocarcinomas (PDACs) as well, but absent from normal exocrine pancreatic tissue. Following, MALT1 shows off to be a specific target in cancer cells of PDAC without affecting regular pancreatic cells. Therefore, we studied the impact of pharmacological MALT1 inhibition in pancreatic cancer and showed promising effects on tumor progression. Mepazine (Mep), a phenothiazine derivative, is a known potent MALT1 inhibitor. Newly, we described that biperiden (Bip) is a potent MALT1 inhibitor with even less pharmacological side effects. Thus, Bip is a promising drug leading to reduced proliferation and increased apoptosis in PDAC cells in vitro and in vivo . By compromising MALT1 activity, nuclear translocation of c‐Rel is prevented. c‐Rel is critical for NF‐κB‐dependent inhibition of apoptosis. Hence, off‐label use of Bip or Mep represents a promising new therapeutic approach to PDAC treatment. Regularly, the Anticholinergicum Bip is used to treat neurological side effects of Phenothiazines, like extrapyramidal symptoms.